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Mechanobiology of Stem Cells: Implications for Vascular Tissue Engineering

Maul, Timothy Michael (2008) Mechanobiology of Stem Cells: Implications for Vascular Tissue Engineering. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Current challenges in vascular medicine (e.g., bypass grafting, stenting, and angioplasty.) have driven the field of vascular regenerative medicine. Bone marrow-derived mesenchymal stem cells (BMMSCs) are adult stem cells which may be a suitable cell source for vascular regenerative medicine applications. While it is well known that BMMSCs readily differentiate into musculoskeletal cells, recent studies have provided evidence for their differentiation into smooth muscle cells (SMCs) and endothelial cells (ECs). We and others have demonstrated the ability of the mechanical stimulus of cyclic stretch to drive BMMSC differentiation towards SMCs in vitro, but a rigorous, systematic analysis of other relevant forces is lacking. The working hypothesis that this work addressed is that mechanical stimuli relevant to the vasculature will guide BMMSC differentiation towards SMCs and ECs. To test this hypothesis, rat BMMSCs were exposed to physiologically relevant magnitudes and frequencies of a Mechanical Panel, which consisted of cyclic stretch, cyclic pressure, and shear stress, each applied in parallel to subcultures of BMMSCs. Quantitative changes in morphology, proliferation, and gene and protein expression were assessed to determine the differential effect of each stimulus in a dose- and frequency-dependant manner. Next, we investigated the importance of the duration of applied stimulation to BMMSC differentiation as well as tissue commitment (i.e., cell plasticity) following mechanical stimulation.Our results demonstrate that mechanical stimulation differentially altered BMMSC morphology, proliferation, and gene and protein expression towards the cardiovascular lineage while limiting expression for other lineages including bone, fat, and chondrocyte. This was particularly evident for cyclic stretch, which caused an elongated, spindle-shape and expression of the SMC proteins alpha-actin, calponin, and myosin heavy chain. Furthermore, we found that cyclic pressure and shear stress tended to increase endothelial gene expression when these stimuli are applied to confluent BMMSCs. While our findings as a whole tended to support our hypothesis, our data indicate that SMC protein expression is more readily increased by mechanical stimulation, and is highly variable, even without associated changes in gene expression. Future work employing systems biology approaches that take into consideration the resulting transcriptional and proteomic changes in BMMSCs from these mechanical stimuli will be necessary to more accurately identify how mechanical stimulation can be used as a tool for regenerative medicine.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Maul, Timothy
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairVorp, David
Committee MemberHuard,
Committee MemberMonga, Satdarshan Smongass@upmc.eduSMONGA
Committee MemberWagner, William Rwagnerwr@upmc.eduWAGNER
Date: 30 January 2008
Date Type: Completion
Defense Date: 1 October 2007
Approval Date: 30 January 2008
Submission Date: 16 October 2007
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Swanson School of Engineering > Bioengineering
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Circular Statistics; Computational Fluid Dynamics; Cyclic Pressure; Cyclic Strain; Cyclic Stretch; Differentiation; Gene Expression; Immunohistochemistry; Mechanical Stimulation; mRNA; PCR; Proliferation; Shear Stress; Morphology; Protein Expression; Western blot
Other ID:, etd-10162007-171731
Date Deposited: 10 Nov 2011 20:03
Last Modified: 19 Dec 2016 14:37


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